Diabetic nephropathy (DN), a microvascular complication of diabetes mellitus (DM), is the main cause of end stage kidney disease worldwide. There is a great need to find animal models of DM and DN that better resemble the physiopathological changes in humans. Both DM and DN are influenced by environmental factors and heredity. The SFBR has approximately 2400 baboons in a pedigreed colony, with a 10 cM linkage map available for 800 of these animals, and additional animals are being currently genotyped. Some baboons in this colony have developed clinical features of type-2 DM and 4 animals biopsied thus far have histological features similar to those found in humans with DN. Preliminary fasting blood glucose (FBG) screening of 478 baboons showed 44% with FBG equal to or > 126 mg/dl. Preliminary screening for microalbuminuria (MA) in 298 animals showed 33.5% of 149 control and 42% of 149 diabetic baboons had MA. One of the control and 3 of the diabetic baboons had proteinuria. A subset of 7 age- and weight- matched female baboons averaging 20 years of age underwent kidney biopsy, 4 diabetics and 3 controls. Diabetic animals had FBG > 126 mg/dl, hemoglobin A1C > 6%, abnormal intravenous glucose tolerance test and normal C-peptide levels. Kidney histology showed that diabetic animals had larger glomeruli, thickened glomerular basement membrane, mesangial matrix expansion and areas of mesangiolysis with early nodule formation. These histological changes closely resemble those of DN in humans, making the type-2 diabetic baboon a useful model of DN. We hypothesize that the characterization of the DN phenotype in genotyped baboons from the pedigree, confirmed by kidney biopsy, will allow us to run a genome-wide linkage analysis to identify genes and chromosomal regions associated with the development and progression of DN. We will conduct a population-wide screening in 1000 animals to study the prevalence of DM and the pattern of microalbuminuria in the baboon. The intrarenal renin-angiotensin system (RAS) is activated in DN, as evidenced by the heightened hemodynamic response to blockade of the RAS in human DN. We will characterize the phenotype of DN in a subset of animals and investigate the kidney expression of components of the RAS and other cytokines and matrix proteins associated with DN. We will then perform a genome-wide search to find and localize quantitative trait loci that influence variation in albuminuria and disease progression. Our goal is to identify early markers of disease progression amenable to intervention.